Functional Variation in VEGF Is not Associated

Rachel M Freathy
1
, Michael N Weedon
1
, Beverley Shields
1
, Graham A Hitman
2
,
Mark Walker
3
, Mark I McCarthy
4
, Andrew T Hattersley
1
, Timothy M Frayling
1
1
Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom.
2
Centre for Diabetes and Metabolic Medicine, Barts and The London Queen Mary’s School of
Medicine and Dentistry. London United Kingdom.
3
School of Clinical Medical Sciences,
University of Newcastle upon Tyne Newcastle upon Tyne, United Kingdom.
4
Oxford Centre for
Diabetes, Endocrinology and Metabolism. Headington, Oxford, United Kingdom
ABSTRACT
Context Vascular endothelial growth factor
(VEGF) is important for pancreatic beta cell
development and function. Common variation
in the VEGF gene is associated with altered
serum concentrations of VEGF and with
several diseases, but its role in type 2 diabetes
is not known. The single nucleotide
polymorphisms C-2578A (rs699947), G-
1154A (rs1570360) and G-634C (rs2010963)
in the 5'-region of VEGF are associated with
altered serum concentrations of the protein.
Objective We performed a large case-control
and family-based study to test the hypothesis
that these variants are associated with type 2
diabetes in a UK Caucasian population.
Participants We genotyped 1,969 cases,
1,625 controls and 530 families for the three
single nucleotide polymorphisms.
Main outcome measures Allele and
genotype frequencies were compared between
cases and controls. Family-based analysis was
used to test for over- or under-transmission of
alleles to affected offspring.
Results Despite good power (80%) to detect
odds ratios of approximately 1.2, there were
no significant associations between single
alleles or genotypes and type 2 diabetes. Odds
ratios (and 95% confidence intervals)
comparing case and control allele frequencies
for single nucleotide polymorphisms C-
2578A, G-1154A and G-634C were 0.97
(0.88-1.07), 0.99 (0.90-1.09) and 0.97 (0.88-
1.08), respectively.
Conclusion This is the first large-scale study
to examine the association between common
functional variation in VEGF and type 2
diabetes risk. We have found no evidence that
these three single nucleotide polymorphisms,
shown previously to alter VEGF
concentrations, are risk factors for type 2
diabetes in a large UK Caucasian case-control
and family-based study.
INTRODUCTION
Vascular endothelial growth factor (VEGF) is
a powerful angiogenic and vascular
permeability factor [1]. The VEGF gene
consists of 8 exons on chromosome 6p21.3
[2]. Human VEGF pre-mRNA undergoes
alternative splicing to give rise to five
polypeptide isoforms of 121, 145, 165, 189
and 206 amino acids, whilst translation from
an alternative initiation codon results in a

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larger isoform (L-VEGF) of 395 amino acids
[3]. Cells producing VEGF include pancreatic
islet, smooth muscle, mesangial, kidney and
various tumour cells, along with
macrophages, keratinocytes and T cells [4].
There is increasing evidence that, as well as
playing a vital role in the development and
differentiation of the vascular system, VEGF
is critical for cell growth in many tissues.
The VEGF protein is important for pancreatic
beta cell development and function. Both
exogenous VEGF administration and genetic
manipulation to increase endogenous VEGF
production promote pancreatic islet
revascularisation and prolong islet survival
and viability after transplantation in mice [5,
6, 7, 8, 9]. Genetic manipulation in mice has
confirmed the key role of VEGF in pancreatic
survival. Firstly, there is an increase in islet
size and vascularisation in transgenic mice
over-expressing Vegfa [10]. Secondly, murine
studies of beta cell-specific Vegfa inactivation
show lower islet vascularisation, a disordered
endothelial structure, and reduced plasma
insulin
levels
following
glucose
administration [11] or the development of
diabetes given a high fat diet to induce insulin
resistance, despite a partial compensatory
increase in islet mass [12].
Common variation in VEGF is associated
with several diseases. Three single nucleotide
polymorphisms (SNPs: C-2578A, G-1154A
and G-634C) in the VEGF promoter and 5'-
UTR are reproducibly associated with
amyotrophic lateral sclerosis (ALS). Meta-
analysis of four European populations showed
that genotypes -2578A/A, -1154A/A and -
634G/G are associated with increased risk of
ALS (recessive model; odds ratios (ORs): 1.4
(95% CI: 1.1-1.8), 1.5 (95% CI: 1.1-2.0) and
1.2 (95% CI: 1.0-1.5), respectively) [13].
There is no obvious link between ALS and
diabetes but these results suggest that the
three SNPs are associated with altered VEGF
function. These results are consistent with the
observation that ALS patients have low serum
VEGF concentrations [13]. There is some
evidence of association between VEGF and
other diseases, including diabetic retinopathy
[14, 15, 16], but these results require further
replication due to small sample sizes. There
have been no association studies between
VEGF and type 2 diabetes risk with a
sufficiently large sample size to detect odds
ratios of about 1.2.
There is strong evidence that SNPs C-2578A,
G-1154A, and G-634C are associated with
altered plasma VEGF concentrations and
altered VEGF gene expression. Healthy
subjects who are either homozygous for the -
1154A [13] allele or who carry at least one
copy of the -634G allele [14] have
significantly reduced plasma VEGF
concentrations. In addition, the AAG and
AGG haplotypes of these SNPs are associated
with lower plasma VEGF concentrations in
two separate Caucasian populations [13]. All
three variants are also associated with VEGF
production from stimulated peripheral blood
mononuclear cells from healthy individuals
[17, 18]. Consistent with the in vivo evidence,
a luciferase reporter assay confirmed that the -
1154A allele reduces transcription by 25%,
while -634G acts post-transcriptionally,
reducing production of the L-VEGF isoform
by 20% [13]. Additional in vitro work in the
same study revealed that the AAG and AGG
haplotypes reduce transcription of luciferase
by 41% and 30%, respectively.
The evidence that VEGF contributes to the
correct functioning of beta cells makes it an
important candidate gene for type 2 diabetes
susceptibility. We hypothesised that SNPs C-
2578A (rs699947), G-1154A (rs1570360),
and G-634C (rs2010963) would be associated
with type 2 diabetes in the UK Caucasian
population. Here we present the results of a
large study examining the role of this
common functional VEGF variation in type 2
diabetes.
METHODS
Subjects for Case/Control Analysis
The clinical characteristics of case and control
subjects are shown in Table 1, arranged by
sub-group. Case subjects were unrelated UK
Caucasians with type 2 diabetes. Cases were
included either if they had type 2 diabetes, as

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defined by World Health Organisation
criteria, or if they were being treated with
medication for diabetes. Clinical criteria
and/or genetic testing were used to exclude
known subtypes of diabetes such as maturity-
onset diabetes of the young or mitochondrial
inherited diabetes and deafness. Cases were
recruited from three sources, as described
previously [19, 20]. These included subjects
with young-onset type 2 diabetes (YT2D; age
at diagnosis 18-45 years; n=284); probands
from type 2 diabetic sibships from the
Diabetes UK Warren 2 repository (n=545)
[21, 22]; and a more recent collection of
subjects with type 2 diabetes from the
Diabetes UK Warren 2 repository (age at
diagnosis 35-65 years; not selected for having
a family history of diabetes; n=1,140). All
affected subjects were negative for GAD
autoantibodies.
Control subjects were unrelated UK
Caucasians recruited from two sources:
parents from a consecutive birth study (Exeter
Family Study of Childhood Health [23];
n=1,154) with normal (less than 6.0 mmol/L)
fasting glucose and/or normal HbA1C (less
than 6%, Diabetes Control and Complications
Trial-corrected) [22] and a nationally
recruited control sample from the European
Collection of Cell Cultures (ECACC)
(n=471).
Subjects for Family-Based Analysis
Families were recruited as part of a Warren 2
cohort from across the UK. The following
criteria were used for inclusion: an affected
proband with both parents or with one parent
and at least one unaffected sibling (89% of
such families included more than two
unaffected siblings). The characteristics of
some of these families have been described
previously [24]. The clinical characteristics of
the affected probands are shown in Table 1.
Using the same case-control and family-based
samples, associations have recently been
shown between the KCNJ11, K23 allele [25],
the HNF4A P2 promoter haplotype [19] and
Table 1. Clinical characteristics of study subjects by group.
Case
subjects
Control
subjects
Family-
based
subjects
Warren 2
cases
Warren 2
probands
YT2D
Exeter
family study
parents
ECACC
human
random UK
controls
Warren 2
families
No. of cases
1,140
545
284
1,154
471
530 families
Gender
- Male
- Female
62%
38%
53%
47%
54%
46%
49%
51%
52%
48%
58%b
42%b
Age (years) a
Median
(Interquartile range)
52
(45-57)
56
(50-61)
40
(35-44)
32
(29-35)
NA
42b
(37-48)b
BMI (kg/m2)
Median
(Interquartile range)
30.7
(27.3-35.1)
28.1
(25.3-31.5)
32.0
(27.8-36.6)
24.7
(22.1-27.9)
NA
32.3b
(28.4-37.3)b
Treatment
- Diet
- Oral hypoglycaemic agents
- Insulin
8%
65%
27%
18%
67%
15%
9%
53%
38%
-
-
18%b
62%b
20%b
Subjects successfully genotyped for at least one single nucleotide polymorphism are included
YT2D: young onset type 2 diabetes
ECACC: European Collection of Cell Cultures
NA: not available
Age at diagnosis for case subjects; age at study for control subjects
Probands only

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the PPARG P12 allele [26] and type 2
diabetes with odds ratios consistent with other
large type 2 diabetes case-control studies and
meta-analyses of multiple studies.
Genotyping and Quality Control
Genotyping was carried out by KBiosciences
(Herts, UK) using its own novel system of
competitive allele specific PCR (KASPar).
Details of assay design are available from
http://www.kbioscience.co.uk. The genotype-
ing was performed in 1,536-well plates
containing cases, controls and families. At
least one negative control well was included
per 96 samples. Nine per cent of the samples
included were duplicates.
Genotyping accuracy, as determined from the
genotype concordance between duplicate
samples, was 99.6%. The mean genotyping
assay success rate was 97.2% for case and
97.5% for control samples. There were no
Mendelian inheritance errors in the family-
based sample.
ETHICS
Informed consent was obtained from all
participants. The study was approved by local
research ethics committee and the protocol
conforms to the ethical guidelines of the
World Medical Association Declaration of
Helsinki.
STATISTICS
Before combining case and control
subgroups, we tested for homogeneity of
genotype and allele frequencies for each SNP
using the chi-square test. Odds ratios and P
values were calculated using chi-square tests
for our case/control analyses. We used
COCAPHASE [27] (available at http://portal.
litbio.org/Registered/Option/unphased.html; last
accessed September 1
st
, 2005) to estimate
haplotype frequencies and perform tests of
haplotype association. This program utilises
the expectation-maximisation algorithm to
account for haplotype uncertainties. To
analyse our family data, we used the family-
based association test (FBAT) program [28,
29] (available at http://www.biostat.harvard.
edu/~fbat/default.html; last accessed October
12
th
, 2005). The transmission disequilibrium
test (TDT/sibTDT) method [30] was used to
confirm the results for single SNPs. Our
sample of 1,969 cases and 1,625 controls gave
us 80% power to detect odds ratios for alleles
of 1.19. This power calculation is for a two-
tailed P value less than 0.01, assuming a
control allele frequency of 0.30 [13].
To assess the degree of linkage disequilibrium
between the SNPs chosen for this study and
other variants across VEGF, the Haploview
package [31] (available at http://www.broad.
mit.edu/mpg/haploview/; last accessed
September 20
th
, 2005) was used to analyse
both our own data and genotype data (Centre
d’Etude du Polymorphisme Humain (CEPH)
trios) from The International HapMap Project
(Phase I and II data combined;
http://www.hapmap.org/index.html.en; last
accessed October 14
th
, 2005).
RESULTS
All three SNPs were in Hardy-Weinberg
equilibrium in cases, controls and family
probands (P>0.102). Hardy-Weinberg
equilibrium was also observed within each
study subgroup of cases and controls, and the
allele and genotype frequencies for each SNP
did not differ significantly between these
subgroups (P>0.091).
Linkage disequilibrium occurred between
SNPs such that only four out of the 8 possible
haplotypes were observed. Pairwise r
2
values
between the three SNPs were all less than 0.5
(maximum r
2
equal to 0.484), meaning that
they provide non-redundant information.
Control allele and haplotype frequencies were
similar to those observed previously [13].
Analysis of HapMap genotype data showed
that the only SNP in this study for which
HapMap genotype data are available (C-
2578A; rs699947) did not capture (at r
2
greater than 0.8) any other of the nine
genotyped SNPs across the 20 kb region
including VEGF.

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Genotype, allele and haplotype frequencies
for cases and controls are displayed in Table
2. Genotype and allele frequencies are shown
separately for each subgroup of cases and
controls in Table 3. There were no significant
associations between single alleles, genotypes
or haplotypes and type 2 diabetes. The result
of a global test of haplotype association was
P=0.792 (haplotypes excluded with frequency
less than 0.05).
The results of the FBAT analysis are
presented in Table 4. There was no significant
over- or under-transmission of alleles or
haplotypes to the affected offspring. A
TDT/sibTDT analysis produced very similar
results for single SNPs.
DISCUSSION
The VEGF gene is a particularly strong type 2
diabetes candidate gene for the following
reasons. First, the protein has an important
role in pancreatic beta cell function [5, 6, 7, 8,
9, 10, 11, 12]. Second, there is strong
evidence that common variation in the gene is
functional [13, 14, 18]. We hypothesised that
SNPs C-2578A, G-1154A and G-634C,
previously associated with altered circulating
VEGF levels, would be associated with
reduced beta-cell function and hence type 2
diabetes. Our case-control and family-based
study results gave no support for this.
Whilst we have not captured all common
variation in VEGF, we have tested variants
suggested in large cohorts to be functional,
and can exclude them from having all but a
minor effect (OR less than 1.14, 1.27 and 1.19
for SNPs C-2578A, G-1154A and G-634C,
respectively) on type 2 diabetes susceptibility.
It is possible that the relatively young age of
our control subjects compared to our cases
reduced our power to detect an association:
Table 2. Results of case/control analysis: distribution of single nucleotide polymorphism alleles, genotypes and
haplotypes in cases and controls.
Genotype or allele
Controls
Cases
P value
OR (95% CI)
-2578CC
381 (25%)
476 (26%)
0.567
1.00
-2578CA
782 (50%)
893 (49%)
0.91 (0.77-1.08)
-2578AA
388 (25%)
455 (25%)
0.94 (0.78-1.14)
-2578C
1,544 (50%)
1,845 (51%)
0.512
1.00
-2578A
1,558 (50%)
1,803 (49%)
0.97 (0.88-1.07)
-1154GG
710 (44%)
858 (45%)
0.859
1.00
-1154GA
731 (46%)
852 (45%)
0.96 (0.84-1.11)
-1154AA
162 (10%)
197 (10%)
1.01 (0.80-1.27)
-1154G
2,151 (67%)
2,568 (67%)
0.832
1.00
-1154A
1,055 (33%)
1,246 (33%)
0.99 (0.90-1.09)
-634GG
732 (46%)
892 (46%)
0.874
1.00
-634GC
700 (44%)
837 (44%)
0.98 (0.85-1.13)
-634CC
168 (11%)
193 (10%)
0.94 (0.75-1.19)
-634G
2,164 (68%)
2,621 (68%)
0.617
1.00
-634C
1,036 (32%)
1,223 (32%)
0.97 (0.88-1.08)
Haplotype
AGG
512 (17%)
590 (17%)
0.908
1.01 (0.88-1.15)
AAG
1,011 (33%)
1,130 (32%)
0.527
0.96 (0.87-1.07)
CGG
541 (18%)
648 (19%)
0.409
1.06 (0.93-1.20)
CGC
978 (32%)
1,098 (32%)
0.622
0.97 (0.87-1.08)
P values (two-tailed) were calculated using chi-square tests with 3x2 contingency tables (genotypes; 2 d.f.) or 2x2
contingency tables (alleles; 1 d.f.). Odds ratios were calculated relative to common homozygous genotypes -2578CC, -
1154GG, -634GG, or the most common alleles -2578C, -1154G, -634G. P values for haplotypes were obtained using
the COCAPHASE program. Odds ratios (ORs) were calculated for each haplotype relative to all others. Haplotypes
were constructed with single nucleotide polymorphisms in the order: C-2578A, G-1154A, G-634C

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some of our controls may yet develop type 2
diabetes. However, this is unlikely to affect
more than 5-10% of Caucasian subjects [32].
In addition, most of our case subjects were
ascertained for family history or young-onset
(or both), which means they are likely to be
enriched for genetic effects. The same data set
has been sufficiently powerful to detect
association for SNPs shown by meta-analysis
to be consistently associated with type 2
diabetes [19, 25, 26]. Serum VEGF
concentrations were not available for our
subjects, so our study is based on the
assumption that the SNPs affect VEGF
production. However, there is robust evidence
for this [13], which is supported by
independent work from two other studies [14,
18].
Table 3. Genotype and allele numbers and frequencies by study and single nucleotide polymorphism.
Case
subjects
Control
subjects
Family-based
subjects
Warren 2
cases a
Warren 2
probands
YT2D
Exeter
family study
parents
ECACC
human
random UK
controls
Warren 2
family
probands
C-2578A
CC
285 (27%)
116 (22%)
75 (28%)
270 (24%)
111 (25%)
116 (23%)
CA
500 (48%)
272 (53%)
121 (45%)
552 (50%)
230 (51%)
269 (52%)
AA
254 (24%)
128 (25%)
73 (27%)
282 (26%)
106 (24%)
129 (25%)
C
1,070 (51%) 504 (49%)
271 (50%)
1,092 (49%) 452 (51%)
501 (49%)
A
1,008 (49%) 528 (51%)
267 (50%)
1,116 (51%) 442 (49%)
527 (51%)
G-1154A
GG
509 (46%)
234 (44%)
115 (42%)
494 (43%)
216 (47%)
226 (44%)
GA
470 (43%)
250 (47%)
132 (48%)
520 (46%)
211 (45%)
246 (47%)
AA
119 (11%)
50 (9%)
28 (10%)
125 (11%)
37 (8%)
48 (9%)
G
1,488 (68%) 718 (67%)
362 (66%)
1,508 (66%) 643 (69%)
698 (67%)
A
708 (32%)
350 (33%)
188 (34%)
770 (34%)
285 (31%)
342 (33%)
G-634C
GG
509 (46%)
256 (48%)
127 (46%)
531 (47%)
201 (44%)
249 (48%)
GC
484 (44%)
237 (44%)
116 (42%)
493 (43%)
207 (45%)
214 (42%)
CC
117 (11%)
43 (8%)
33 (12%)
118 (10%)
50 (11%)
51 (10%)
G
1,502 (68%) 749 (70%)
370 (67%)
1,555 (68%) 609 (66%)
712 (69%)
C
718 (32%%) 323 (30%)
182 (33%)
729 (32%)
307 (34%)
316 (31%)
For C-2578A, 90 samples were missed and therefore not genotyped. Calculation of genotype assay success rate was
adjusted accordingly
Table 4. Results of FBAT analysis of association of haplotypes and single single nucleotide polymorphism alleles with
type 2 diabetes in the family-based sample.
Allele/Haplotype
Frequency
Number of
informative
families
Observed
transmissions
Expected
transmissions
Z
P
-2578C
51%
319
328
331
-0.29
0.769
-1154A
33%
290
228
223
0.47
0.638
-634C
34%
268
213
221
-0.91
0.365
AAG
32%
239
229
230
-0.13
0.893
CGC
32%
228
227
232
-0.57
0.569
CGG
18%
177
152
144
1.10
0.273
AGG
17%
183
133
133
-0.05
0.959
Haplotypes were constructed with single nucleotide polymorphisms in the order: C-2578A, G-1154A, G-634C.

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Finally, we have not assessed the role of these
polymorphisms in relevant continuous traits,
such as measures of insulin secretion. We
would expect the potential relationship to be
with reduced insulin secretion, due to reduced
beta-cell function. Further studies, consisting
of large numbers of subjects with oral glucose
tolerance test data, will be needed to test this.
In conclusion, this is the first large-scale
study to examine the association between
common functional variation in VEGF and
type 2 diabetes. We have examined
polymorphisms associated in several studies
with altered VEGF concentrations, but found
no evidence that they are involved in the
genetic susceptibility to type 2 diabetes in our
large case-control and family-based study.
Received January 16
th
, 2006 - Accepted April
11
th
, 2006
Keywords
Association; Polymorphism,
Single Nucleotide; Vascular Endothelial
Growth Factor A
Abbreviations ALS: amyotrophic lateral
sclerosis; CEPH: Centre d’Etude du
Polymorphisme Humain; ECACC: European
Collection of Cell Cultures; FBAT: family-
based association test; SNP: single nucleotide
polymorphism;
TDT:
transmission
disequilibrium test; VEGF: vascular
endothelial growth factor; YT2D: young-
onset type 2 diabetes
Acknowledgements RM Freathy holds a
Diabetes UK research studentship. AT
Hattersley is a Wellcome Trust Research
Leave Fellow
Correspondence
Timothy M Frayling
Institute of Biomedical and Clinical Science
Peninsula Medical School
Magdalen Road
Exeter, EX1 2LU
United Kingdom
Phone: +44-1392.262.935
Fax: +44-1392.262.926
E-mail: tim.frayling@pms.ac.uk
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